Project Summary The goal of this F31 NRSA project is to develop new methods to focus ultrasound through the skull. The methods would enable rapid, in vivo refocusing of magnetic resonance imaging (MRI)-guided transcranial focused ultrasound (FUS) pressure fields for ultrasonic neuromodulation, which is currently limited in the achievable specificity and safety for neuromodulation due to skull-induced aberrations of the pressure field. An ideal refocusing method for MRI-guided transcranial FUS would be safe, rapid, and capable of compensating for any skull with in situ measurements. Current clinical implementations of transcranial FUS use a pretreatment computed tomography (CT) scan of the patient?s skull to derive a map of skull acoustic properties for refocusing, but this method has been shown to fail in some patients due to inaccuracies in the mapping procedure, preventing treatment in those patients. CT scans also require a radiation dose. The methods proposed in this application overcome existing limitations in transcranial refocusing methods using magnetic resonance imaging acoustic radiation force imaging (MRI ARFI). MRI ARFI scans indirectly map the pressure field in situ via motion-encoding gradients synchronized with a safe, low duty cycle ultrasound pulse. Transcranial refocusing with MRI ARFI has conventionally been applied by observing the MRI ARFI-derived signal in a single image voxel after a number of distinct ultrasound emissions, but this requires long scan times that have prohibited its use in vivo. The methods proposed in this project use MRI ARFI in a multi-voxel approach with magnitude least squares optimization to more efficiently refocus the pressure field. In simulations, I have demonstrated that it may be possible to achieve transcranial refocusing with just a single MRI ARFI acquisition. The central innovation in this project is to use a multi-voxel MRI ARFI-based approach for refocusing pressure fields generated by MRI-guided transcranial FUS in less than ten minutes. The first Aim is to implement multi-voxel refocusing using hydrophone and ex vivo experimental platforms. The second Aim is to optimize and evaluate multi-voxel refocusing in ex vivo experiments, with further validation in an in vivo non-human primate animal model developed by our group for this and other ultrasonic neuromodulation experiments. The first and second Aims will use our group?s 128 element transcranial FUS system custom-designed for ultrasonic neuromodulation in non-human primates. The third Aim is to evaluate multi-voxel refocusing in ex vivo experiments using the Insightec ExAblate Neuro, which is a clinical 1024 element transcranial FUS system. By refocusing the pressure field in less than ten minutes, this project will fundamentally enable highly specific, non- invasive ultrasonic neuromodulation in a broad human population.